JPS585911B2 - (2-oxo-pyrrolidine-1) -acetamido - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing (2-oxo-pyrrolidine-1)-acetamide.

(2-Oxo-pyrrolidine-1)-acetamide has recently been used under the generic name Piracetam as a medicine against motion sickness and for the treatment of senile regression [Ar. Yacht. A.J. Stegink
Arzne Mitstelf Orschung (Arzne Mitstelf Orschung)
imittelforschung) Volume 22 (197
2, No. 6), pp. 975-977], and furthermore, psychotropic drugs that have a positive effect on intellectual ability (nootr.
opes Mittel), Strehl), Ar. Proswitz (A. Bros.
switz)
ewoche), Vol. 26, p. 2975 (1972)].

(2-oxo-pyrrolidine-1)-acetamide is (
It has already been shown in DE 16 20 608 that 2-oxo-pyrrolidine-1)-acetic acid ethyl ester can be prepared by amidation with ammonia.

However, the product obtained by this method has very low purity and must be recrystallized many times for purification.

Such purification not only requires excessive technical effort but also significantly reduces the yield of the target product.

Furthermore, in this conventional method, ammonia is used in large excess;
That is, more than 10 times the stoichiometric amount for this reaction must be used.

Therefore, for every mole of (2-oxo-pyrrolidine-1)-acetamide, more than 9 moles of ammonia are wasted.
Post-processing and/or removal requires a lot of effort.

Furthermore, this conventional method requires a considerably large amount of solvent, so the technical and economic burden in this respect is also a disadvantage that cannot be overlooked.

Another problem with this conventional method is that ammonia is always introduced in gaseous form during the reaction, which makes the equipment difficult to operate and the environment Risk of contamination arises.

The present inventor has conducted research with the aim of providing a simple and smooth method for obtaining (2-oxo-pyrrolidine-1)-acetamide represented by the following formula (■) in high yield, and has The task is the following formula (■)
: (wherein, R1 represents a hydrogen atom or a group represented by the following formula (■):).

They have found that the problem can be solved by a method characterized by reducing (2-oxo-pyrrolidine-1)-acetic acid hydrazide represented by (2-oxo-pyrrolidine-1) or a mixture of these hydrazides.

The compound of formula (II) serving as the starting material of the present invention is a compound of the following formula (
(2): (2-oxo-pyrrolidine-1)-acetic acid ester of (wherein R2 represents a lower alkyl group having 1 to 4 carbon atoms) is converted into hydrazine or formula (n) where R1 represents a hydrogen atom
It is produced by reacting with a hydrazine derivative of

A particularly preferred reduction method is catalytic hydrogenation using molecular hydrogen (H2) in the presence of a hydrogenation catalyst.

This hydrogenation reaction takes place between 5 and 30 atm gauge (atu).
) at an elevated temperature under a pressure of (preferably 80 to 150
℃) in an organic solvent.

Preferred organic solvents are methanol, ethanol, ingropanol and/or butanol (including isomers).

This catalytic hydrogenation with molecular hydrogen (H2) is carried out in the presence of a conventional hydrogenation catalyst.

Such hydrogenation catalysts include, for example, Raney catalysts (such as Raney nickel), earth metal catalysts supported on supports (such as palladium, platinum, rhodium or ruthenium on carbon), and suitable supports. Any other catalytically active metal supported on the catalyst, or known metal complex catalysts or skeletal catalysts may be used.

In order to reduce the hydrazide of formula (■), methods other than the hydrogenation described above can also be used.

For example, lithium alanate
at), that is, a method of reduction using lithium aluminum hydride (which is usually used in the form of an ether solution), a method of reduction using a zinc/hydrochloric acid system or a similar system in a corresponding solvent, etc. are suitable. This is a great method.

However, catalytic hydrogenation is the best reduction method.

Hydrogenation is usually carried out under pressure in a pressure vessel, but
In consideration of reaction speed, a low pressure of 5 to 10 atm gauge is usually used.

The method of the invention uses relatively little solvent and the reaction can be carried out in conventional equipment.

As the solvent, lower alkanols from methanol to butanol (including isomers) are particularly suitable, with methanol being particularly preferred.

Methanol is preferred because the hydrazide of formula (■) is highly soluble in methanol, especially at the high temperatures required for hydrogenation.

After the reaction is complete, if the mother liquor is recovered without evaporating the solvent, it is possible to return the mother liquor as it is to the reaction system or to reuse it in a new batch of reaction.

The method of the present invention furthermore provides two hydrazides of formula (■), namely (2-oxo-pyrrolidine-1)-acetic acid hydrazide of formula (■a): and (2-oxo-pyrrolidine-1)-acetic acid hydrazide of formula (■b): Among them, R2 represents a group represented by the above formula (■).

), or a mixture of the compound of formula (■a) and the compound of formula (■b). Starting from either of them, the desired acetamide can be obtained in virtually quantitative yield, for example by catalytic hydrogenation.

That is, 1 mole of the desired acetamide can be obtained from 1 mole of the compound of formula (■a), and 2 moles of the desired acetamide can be obtained from 1 mole of the compound of formula (■b).

When a mixture of these two hydrazides is used, the yield is calculated in each case.

Furthermore, in any of the above cases, the purity of the acetamide target product obtained is extremely high.

Since the target substance exists in the form of a solution especially when the temperature is high, it is very easily separated from the catalyst by filtration.

The catalyst thus recovered can be used for multiple reactions.

This is because the starting material, the hydrazide of formula (■), is already in very pure form and does not cause catalyst poisoning.

After removing the catalyst, the solution is cooled, preferably with addition of inpropanol, and the desired acetamide precipitates in the form of colorless crystals.

This can be isolated by any known method, such as collecting a precipitate by filtration, washing it with, for example, isopropanol, and drying it.

The acetamide of formula (I) thus obtained is found to be very pure, based on the results of its thin layer chromatography analysis and its very narrow melting point range (151-152°C). I understand.

For comparison, acetamide of formula (I) was also produced by a known method, and the melting point of this acetamide was also 151-1.
The temperature was 52°C.

The major advantages brought about by the method of the present invention include the need for a small amount of solvent and the use of an easy-to-implement catalytic hydrogenation reaction, as well as the fact that an extremely pure target product can be obtained without a single recrystallization. One example is that it can be used directly for pharmaceutical applications as mentioned above.

Furthermore, whereas the conventional method obtains (2-oxo-pyrrolidine-1)-acetamide by amidating (2-oxo-pyrrolidine-1)-acetate ethyl ester with a large excess of ammonia, the present invention According to the authors, another great feature of the present invention is that it is possible to avoid the use of ammonia, which has always been a major obstacle in terms of technical control.

EXAMPLES Hereinafter, the present invention will be explained in more detail based on Examples, but the present invention is not limited thereto.

Example 1 (2-oxopyrrolidine-1)-acetic acid hydrazide 15
Dissolve 7g (1 mol) in 400ml of anhydrous methanol,
This solution was put into a pressure vessel together with 10 g of Raney nickel, the vessel was sealed, the pressure was 20 bar gauge, the temperature was 100~
The hydrogenation reaction was carried out at 120° C. until absorption of hydrogen gas stopped.

After completion, the pressure vessel was opened and the mixture was filtered hot to remove the catalyst (the catalyst thus recovered can be used as catalyst for the second and subsequent batches).

) The filtrate was then concentrated, 400 ml of isopropanol was added to the still quite hot concentrate and the mixture was cooled while stirring.

Finally, suction filtration and washing with isopropanol were performed to obtain 140 g (2-oxo-pyrrolidine-1)-acetamide (89% of theoretical yield) in the form of colorless crystals.

The melting point of this product was 151°C.

This mother liquor can be used in its original form many times in new batches.

The yield in that case rose to 96%.

When the acetamide thus obtained was subjected to nitrogen analysis, the following values were obtained.

Calculated value (%) Actual value (%) N: 19.72% 19.73% Example 2 282 g (1 mol) of 1,2-bis(2'-oquine-pyrrolidine-1')-acetic acid hydrazide was added to methanol. 700
ml, using 20 g of Raney nickel as a catalyst, hydrogen pressure 2
Hydrogenation was carried out under conditions of 0 atmospheric pressure gauge and temperature of 100 to 120°C until saturation.

After completion, the product mixture is filtered hot to remove the catalyst (the catalyst thus recovered can be used in the next reaction).

), the filtrate was concentrated, 800 ml of ingropanol was added to the hot concentrate, and the mixture was cooled with stirring.

Then, by suction filtration and washing with isopropanol, (2-oxo-pyrrolidine-1)-acetamide 25
0 g (88% of theoretical yield) was obtained in the form of colorless crystals.

The melting point of this product was 151-152°C.

When the mother liquor was used for the second and subsequent batches, the yield was 9.
．． It rose to 6%.

When the acetamide thus obtained was subjected to elemental analysis for nitrogen, the following values were obtained.

Calculated value (%) Actual value (%) N: 19.72% 19.71% Example 3 (2-Oquine-pyrrolidine-1)-acetic acid hydrazide 15
7 g (1 mol) and 282 g (1 mol) of 1,2-bis(2'-oxo-pyrrolidine-1'-)-acetic acid hydrazide.
was dissolved in 1100 ml of methanol, and 40 g of Raney nickel was added thereto.

Next, a hydrogenation reaction was carried out under the conditions of a temperature of 150° C. and a hydrogen pressure of 15 atm gauge until saturation was reached.

After completion, the product mixture is filtered hot to remove the catalyst (the catalyst thus recovered can be reused in subsequent batches).

), the filtrate was concentrated and 1200 ml of inpropanol were added to the concentrate while it was still hot, after which the mixture was cooled with stirring.

Finally, it was filtered with suction and the collected product was washed with isopropanol to give (2-oxo-pyrrolidine-1)
392 g (88% of theoretical yield) of acetamide were obtained in the form of colorless crystals.

Melting point: 151-152°C. When the mother liquor was used directly in subsequent batches, the yield increased to 96%.

When the acetamide thus obtained was subjected to elemental analysis for nitrogen, the following values were obtained.

Calculated value (%) Actual value (%) N: 19.72% 19.73%

Claims (1)

[Claims] Primary formula (■): (In the formula, Rl represents a hydrogen atom or a group represented by the following formula (■):) or a mixture of the two is reduced. (2
-Oxo-pyrrolidine-1)-acetamide manufacturing method.